This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Osteopenia and bone fractures complicate the clinical course of girls and women with Rett syndrome (RTT). Our studies show that total body bone mineral content (BMC) is below -1 SD and -2 SD in 82% and 57% of these individuals, respectively (1). The purpose of this study is to determine the efficacy of oral calcium (Ca) supplementation in the treatment of osteopenia in RTT girls and women. We hypothesize that oral Ca supplementation will reverse the progression of bone mineral loss in RTT girls and women, particularly in younger than older individuals, by reducing bone mineral resorption and increasing bone mineral deposition. To test this hypothesis, we will measure BMC using duel energy x-ray absorptiometry (DXA) in 54 RTT girls and women randomized to receive oral Ca supplements or placebo. Urinary Ca excretion and venous markers of Ca metabolism will be measured. Bone fracture prevalence will be documented by medcal history and ambulatory status will be scored by clinicalexamination. Stadiometric and anthropometric measurements will be performed to characterize growth and regional muscle mass. Three-day food records and interval pill count will be obtained to monitor compliance. We anticipate that BMC z-scores will increase and urinary Ca wasting will decrease with oral Ca supplementation thereby reversing the progression of bone mineral loss in RTT girls and women. This information will be important to ascertain because of the longevity of RTT girls and women and the need to provide interventional strategies that prevent the adverse consequences associated with osteopenia. HYPOTHESIS The purpose of this study is to determine the therapeutic efficacy and safety of oral Ca supplementation in the treatment of osteopenia inRTT girls and women. We hypothesize that oral Ca supplementation will reverse the progression of bone mineral loss, particularly in younger than in older individuals, by decreasing bone mineral resorption and increasing bone mineral deposition in RTT girls and women. SPECIFIC AIMS 1. To determine if oral Ca supplements result in a greater increase in absolute BMC and BMC z-scores, measured byDXA, than placebo inRTT girls and women 2. To determine if Ca supplements result in a greater increase in absolute BMC and BMC z-scores in pre-pubertal RTT girls than in post-pubertal RTT women 3. To determine if oral Ca supplements result in a greater reduction in bone mineral resorption, measured by N-telopeptides and urinary Cacreatinine ratios, than placebo in RTT girls and women 4. To determine if oral Ca supplements result in increased bone mineral deposition, measured by osteocalcin and bone alkaline phosphatase, than placebo in RTT girls and women.